DESCRIPTION: The objective of the proposed research is to investigate synthetic mimetics of the natural proteoglycan lubricant, lubricin, to delay or prevent progression of osteoarthritis following injury to the weight bearing articular cartilage of the knee. Hyaluronic acid is a polysaccharide that is the natural hydrodynamic mode lubricant (fast and light normal load) in the knee. Lubricin is a proteoglycan that is the natural boundary mode lubricant (slow and heavy normal load) in the knee. Both hydrodynamic and boundary mode lubrication are essential, but not yet clinically available, to adequately lubricate the knee and to delay or prevent OA progression. This is the focus of the proposed research. The hypothesis is that boundary mode lubrication of the knee can be afforded by synthetic lubricin mimetics, and that intraarticular administration of the mimetics will prevent OA disease progression. Our hypothesis will be evaluated in the experiments of the following Specific Aims: Specific Aim 1: To quantify how the molecular architecture of synthetic lubricin mimetics correlates to boundary mode lubrication on cartilage. A library of synthetic lubricin mimetics, specifically brush copolymers of polyacryli acid-graft-polyethylene glycol, will be synthesized and characterized with serial alterations in their backbone molecular weight, side chain molecular weight and side chain density. The boundary mode lubrication characteristics of each brush copolymer will be quantified. The anticipated outcome of Specific Aim 1 is a quantitative understanding of how the molecular architecture of the synthetic lubricin mimetics correlates to their ability to lubricate cartilage under boundary mode conditions. Specific Aim 2: To quantify how cartilage matrix binding peptides tethered to the synthetic lubricin mimetics influence boundary mode lubrication on cartilage. A series of cartilage binding peptides will be tethered to the backbone terminus of the synthetic lubricin mimetics and the lubrication characteristics will be quantified. The anticipated outcome of Specific Aim 2 is a quantitative understanding of how the cartilage binding peptides influence lubricin-mimetic binding kinetics and binding constants, and how these collective parameters influence boundary mode lubrication. Specific Aim 3: To quantify the prevention of OA progression of synthetic lubricin mimetics in an anterior cruciate ligament transection model in Sprague-Dawley rats. The ability of synthetic lubricin mimetics identified from Specific Aims 1 and 2 will be evaluated in a rigorous ACL transection model. The anticipated outcome of Specific Aim 3 will be the identification of one or more clinically promising lubricin mimetics wit the potential to delay or prevent the onset of OA. The anticipated outcome of the proposed research will be the identification of one or more clinically promising lubricin mimetics with the clinical potential to delay or prevent the onset of osteoarthritis.